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Iron In Cancers

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ironjustice

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Dec 13, 2009, 1:35:56 AM12/13/09

"Breast cancer, renal carcinoma, neuroepithelioma, melanoma,
mantle cell lymphoma"

Cell Cycle Regulation by Iron: Novel Approaches to Mantle Cell
Lymphoma Therapy.
Blood (ASH Annual Meeting Abstracts) 2009 114: Abstract 2515
Heather Gilbert, MD1, John Cumming*,2 and Josef T. Prchal, MD3
1 Hematology, University of Utah School of Medicine, Salt Lake Cty,
UT, USA,
2 Hematology, University of Utah School of Medicine, Salt Lake City,
UT, USA,
3 University of Utah, Salt Lake City, UT, USA

Abstract 2515

Poster Board II-492

Mantle cell lymphoma is a well defined subtype of B-cell
non-Hodgkin lymphoma characterized by a translocation that
juxtaposes the BCL1 gene on chromosome 11q13 (which encodes
cyclin D1) next to the immunoglobulin heavy chain gene
promoter on chromosome 14q32.
The result is constitutive overexpression of cyclin D1
(CD1) resulting in deregulation of the cell cycle and
activation of cell survival mechanisms.
There are no "standard" treatments for MCL.
Despite response rates to many chemotherapy regimens of
50% to 70%, the disease typically progresses after treatment,
with a median survival time of approximately 3-4 years.
Mantle cell lymphoma represents a small portion of malignant
lymphomas, but it accounts for a disproportionately large
percentage of lymphoma-related mortality.
Novel therapeutic approaches are needed.
In 2007, Nurtjaha-Tjendraputra described how iron chelation
causes post-translational degradation of cyclin D1 via von
Hippel Lindau protein-independent ubiquitinization and
subsequent proteasomal degradation (1).
Nurtjaha-Tjendraputra demonstrated that iron chelation
inhibits cell cycle progression and induces apoptosis
via proteosomal degradation of cyclin D1 in various cell
lines, including breast cancer, renal carcinoma,
neuroepithelioma and melanoma.
Our preliminary data show similar findings in mantle cell
lymphoma.
To establish whether iron chelation can selectively inhibit
and promote apoptosis in mantle cell derived cell lines, the
human MCL cell lines Jeko-1, Mino, Granta and Hb-12; the
Diffuse Large B cell lymphoma line SUDHL-6; and the Burkitt's
Lymphoma lines BL-41 and DG75 were grown with media only, with
two different iron chelators (deferoxamine (DFO) and deferasirox)
at various concentrations (10, 20, 40, 100 and 250 µM), and with
DMSO as an appropriate vehicle control.
Cells were harvested at 24, 48 and 72 hours.
For detection of apoptotic cells, cell-surface staining was
performed with FITC-labeled anti–Annexin V antibody and PI
(BD Pharmingen, San Diego, CA).
Cell growth was analyzed using the Promega MTS cytotoxicity assay.
CD1 protein levels were assessed using standard Western blot
techniques. At 24, 48 and 72 hours of incubation with iron
chelators, the mantle cell lymphoma cell lines showed
significantly increased rates of apoptosis compared to the
non-mantle cell lymphoma cell lines (p<0.0001 for all time points).
DFO and deferasirox inhibted cell growth with an IC50 of 18 and
12 µM respectively.
All of the mantle cell lines had measurable cyclin D1 levels at
baseline.
None of the non-mantle cell lines expressed baseline measurable
cyclin D1.
In the mantle cell lines, cyclin D1 protein levels were no longer
apparent on western blot after 24 hours of incubation with
chelation.
We then added ferrous ammonium sulfate (FAS) to DFO in a 1:1
molarity ratio and to deferasirox in a 2:1 ratio, and then treated
the same lymphoma cell lines with the FAS/chelator mixture and with
FAS alone for 72 hours.
Adding iron to the chelators completely negated all the pro-apoptotic
effects that were seen with iron chelation treatment.
Treating with FAS alone had no effect on cell growth or apoptosis.
Iron chelation therapy with both DFO and deferasirox results in
decreased cell growth, increased cellular apoptosis, and decreased
cyclin D1 protein levels in vitro in mantle cell lymphoma.
The cytotoxic effects are prevented by coincubation with ferrous
ammonium citrate, confirming that the effects are due to iron
depletion.
Proposed future research includes further defining the molecular
basis of iron chelation effects; studying these therapies in
combination with other cancer treatments both in vitro and in vivo;
and studying iron chelation therapy in mantle cell lymphoma patients.
1. Nurtjahja-Tjendraputra, E., D. Fu, et al. (2007).
"Iron chelation regulates cyclin D1 expression via the proteasome:
a link to iron deficiency-mediated growth suppression."
Blood 109(9): 4045–54.

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Tom

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Ken

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Dec 13, 2009, 12:01:19 PM12/13/09

Maybe Chung has been injesting a bit too much of Rusty?

ironjustice

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Dec 13, 2009, 1:00:23 PM12/13/09

On Dec 12, 10:35 pm, ironjustice <teamtan...@hotmail.com> wrote:
Iron chelation therapy <<

Maltol is a naturaliron-chelating sugar found in your food ..

"Maltol a sugar used as a common food additive"

Comparative study of iron mobilization from haemosiderin, ferritin
and iron(III) precipitates by chelators.
Kontoghiorghes GJ, Chambers S, Hoffbrand AV.
The heteroaromatic chelators 1,2-dimethyl-3-hydroxypyrid-4-one,
MALTOL , mimosine and 2,4-dihydroxypyridine-N-oxide, have been shown
to
mobilize iron from human spleen haemosiderin, ferritin and also from
iron(III) precipitates, all containing equal amounts of iron, at
physiological pH.
In the case of almost every chelator, the least-solubilized
polynuclear iron form was ferritin, whereas haemosiderin was more
soluble and the iron(III) precipitate the most soluble of all.
Most of the chelators were more efficient than desferrioxamine at
releasing iron from ferritin, but less efficient in the removal of
iron from the other two polynuclear iron forms.
It is suggested that the chelator differences in iron mobilization
may be related to variations in the chelator molecular structure, the
protein structure, iron forms and in the mechanism of iron release.

PMID: 3566714
-----------------------

"Chelators of synthetic or plant origin may carry less risk"

The effect of synthetic iron chelators on bacterial growth in human
serum
J.H. Brock a , Joan Licéaga a G.J. Kontoghiorghes b
a University Department of Bacteriology and Immunology, Western
Infirmary, Glasgow, USA b Department of Haematology, Royal Free
Hospital, London, U.K.
Correspondence to: Dr. J.H. Brock, Dept. of Bacteriology and
Immunology, Western Ifirmary, Glasgow, G11 6NT, Scotland, U.K.

ABSTRACT
Abstract The effect of synthetic iron chelators of the 1-alkyl-3-
hydroxy-2-methylpyrid-4-one class (the L1 series) and 1-
hydroxypyrid-2- one (L4) on bacterial growth in human serum was
compared with those of the plant iron chelators mimosine and maltol
and of the microbial siderophore desferrioxamine.
None of the synthetic chelators enhanced growth of 3 Gram-negative
organisms (Yersinia enterocolitica, Escherichia coli and Pseudomonas
aeruginosa); in some cases they were even inhibitory. L4 strongly
stimulated growth of Staphylococcus epidermidis, but the L1 series
had only a marginal effect.
Maltol was mildly inhibitory to all 4 bacterial species, while
mimosine enhanced the growth of S. epidermidis and Y. enterocolitica
but had little effect on E. coli or P. aeruginosa.
Desferrioxamine enhanced the growth.
Chelators of synthetic or plant origin may carry less risk of
increasing susceptibility to bacterial infection in patients
undergoing chelation therapy for iron overload than does
desferrioxamine, the drug currently in clinical use.
Copyright 1988 Federation of European Microbiological Societies
KEYWORDS
Iron * Chelator * Bacterial growth * Infection

FEMS Microbiology Letters
Volume 47 Issue 1, Pages 55 - 60
Published Online: 27 Mar 2006

Received 23 September 1987, Accepted 4 November 1987

DIGITAL OBJECT IDENTIFIER (DOI)
10.1111/j.1574-6968.1988.tb02490.x About DOI

---------------------------

http://www.jbc.org/cgi/reprint/184/1/131.pdf

The formation of maltol upon heating certain aqueous
carbohydrate glycine systems has been investigated.
Carbohydrates used in the experiment included starch,
cellulose, sucrose, lactose, maltose, glucose, galactose,
and methyl a-n-glucopyranoside.
Of these, maltol was obtained from only lactose and maltose.

--------------------------
The Concise Encyclopedia of Foods & Nutrition
Formation and Occurence of Maltol
Chemists have demonstrated that maltol may be formed by heating
maltose at 375 degrees F for 1 hour ( note the similaritiies of these
conditions to those in baking), or by heating mixtures of sugars ,
such as maltose and lactose with amino acids , such as glycine (the
latter procedure is known as nonenzymatic browning reaction of the
Maillard type).
Maltol is found in roasted materials which have a moderate to high
carbohydrate content, such as bread crusts, cocoa beans , cellulose ,
cereals , chicory , coffee beans , diastatic flour doughs ( where
some
of the starch has been convertd by enzyme action to maltose), malt
products, soft woods , and soybeans.
It is also found in heated products which contain moderate amounts of
both sugars and amino acids, such as condensed and dried milks, dried
whey , and soy sauce.
Apparently heating is not always required for the production of
maltol, since it also occurs in larch bark and the dry needles of
cone- bearing evergreen trees.